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3,4-diaminobenzoic acid derivatives as inhibitors of the oxytocinase subfamily of m1 aminopeptidases with immune-regulating properties

3,4-diaminobenzoic acid derivatives as inhibitors of the oxytocinase subfamily of m1 aminopeptidases with immune-regulating properties
3,4-diaminobenzoic acid derivatives as inhibitors of the oxytocinase subfamily of m1 aminopeptidases with immune-regulating properties

Members of the oxytocinase subfamily of M1 aminopeptidases (ERAP1, ERAP2, and IRAP) play important roles in both the adaptive and innate human immune responses. Their enzymatic activity can contribute to the pathogenesis of several major human diseases ranging from viral and parasitic infections to autoimmunity and cancer. We have previously demonstrated that diaminobenzoic acid derivatives show promise as selective inhibitors for this group of aminopeptidases. In this study, we have thoroughly explored a series of 3,4-diaminobenzoic acid derivatives as inhibitors of this class of enzymes, achieving submicromolar inhibitors for ERAP2 (IC50 = 237 nM) and IRAP (IC50 = 105 nM). Cell-based analysis indicated that the lead compounds can be effective in downregulating macrophage activation induced by lipopolysaccharide and interferon-γ as well as cross-presentation by bone marrow-derived dendritic cells. Our results indicate that this class of inhibitors may be useful for the targeted downregulation of immune responses.

0022-2623
1524-1543
Papakyriakou, Athanasios
939bc8c9-1693-4530-9099-c55772b22f1d
Zervoudi, Efthalia
7026d821-247b-4776-90ad-6f27a2ea1eaf
Tsoukalidou, Sofia
8d2224eb-6b2f-4b40-b5f9-e6443d4e9785
Mauvais, Francois Xavier
2378542b-7332-4d04-958a-659d7c7b56f0
Sfyroera, Georgia
ba7f05f8-edcb-4040-93dd-c22ea9744e69
Mastellos, Dimitrios C.
4c42c140-af0e-4cf6-a12d-62a832cbfc70
Van Endert, Peter
17d8b50b-53a0-4064-b054-bd42f425acf4
Theodorakis, Emmanuel A.
2c89ff49-3761-4fa1-b282-e681cc33002c
Vourloumis, Dionisios
124a123e-77d0-496a-b624-a5da2cd7b8dc
Stratikos, Efstratios
85f4a2e4-422a-4dab-a067-f50ea7238c00
Papakyriakou, Athanasios
939bc8c9-1693-4530-9099-c55772b22f1d
Zervoudi, Efthalia
7026d821-247b-4776-90ad-6f27a2ea1eaf
Tsoukalidou, Sofia
8d2224eb-6b2f-4b40-b5f9-e6443d4e9785
Mauvais, Francois Xavier
2378542b-7332-4d04-958a-659d7c7b56f0
Sfyroera, Georgia
ba7f05f8-edcb-4040-93dd-c22ea9744e69
Mastellos, Dimitrios C.
4c42c140-af0e-4cf6-a12d-62a832cbfc70
Van Endert, Peter
17d8b50b-53a0-4064-b054-bd42f425acf4
Theodorakis, Emmanuel A.
2c89ff49-3761-4fa1-b282-e681cc33002c
Vourloumis, Dionisios
124a123e-77d0-496a-b624-a5da2cd7b8dc
Stratikos, Efstratios
85f4a2e4-422a-4dab-a067-f50ea7238c00

Papakyriakou, Athanasios, Zervoudi, Efthalia, Tsoukalidou, Sofia, Mauvais, Francois Xavier, Sfyroera, Georgia, Mastellos, Dimitrios C., Van Endert, Peter, Theodorakis, Emmanuel A., Vourloumis, Dionisios and Stratikos, Efstratios (2015) 3,4-diaminobenzoic acid derivatives as inhibitors of the oxytocinase subfamily of m1 aminopeptidases with immune-regulating properties. Journal of Medicinal Chemistry, 58 (3), 1524-1543. (doi:10.1021/jm501867s).

Record type: Article

Abstract

Members of the oxytocinase subfamily of M1 aminopeptidases (ERAP1, ERAP2, and IRAP) play important roles in both the adaptive and innate human immune responses. Their enzymatic activity can contribute to the pathogenesis of several major human diseases ranging from viral and parasitic infections to autoimmunity and cancer. We have previously demonstrated that diaminobenzoic acid derivatives show promise as selective inhibitors for this group of aminopeptidases. In this study, we have thoroughly explored a series of 3,4-diaminobenzoic acid derivatives as inhibitors of this class of enzymes, achieving submicromolar inhibitors for ERAP2 (IC50 = 237 nM) and IRAP (IC50 = 105 nM). Cell-based analysis indicated that the lead compounds can be effective in downregulating macrophage activation induced by lipopolysaccharide and interferon-γ as well as cross-presentation by bone marrow-derived dendritic cells. Our results indicate that this class of inhibitors may be useful for the targeted downregulation of immune responses.

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e-pub ahead of print date: 18 January 2015
Published date: 12 February 2015

Identifiers

Local EPrints ID: 413238
URI: http://eprints.soton.ac.uk/id/eprint/413238
ISSN: 0022-2623
PURE UUID: b99ff661-8a3e-46db-8cc0-84529297e0e2
ORCID for Athanasios Papakyriakou: ORCID iD orcid.org/0000-0003-3931-6232

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Date deposited: 17 Aug 2017 16:31
Last modified: 06 Jun 2024 01:58

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Contributors

Author: Athanasios Papakyriakou ORCID iD
Author: Efthalia Zervoudi
Author: Sofia Tsoukalidou
Author: Francois Xavier Mauvais
Author: Georgia Sfyroera
Author: Dimitrios C. Mastellos
Author: Peter Van Endert
Author: Emmanuel A. Theodorakis
Author: Dionisios Vourloumis
Author: Efstratios Stratikos

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